Employing Photocatalysis for the Design and Preparation of DNA‐Encoded Libraries: A Case Study

Abstract

This Personal Account describes the authors’ foray into DNA‐encoded libraries. The article addresses several key aspects of this hit generation technology, from the development of new synthetic methodology to the subsequent conception, design, and delivery of a DNA‐encoded library. In particular, we have been engaged in adapting photocatalytic reactions to the idiosyncratic requirements of DNA‐encoded chemistry. We have chosen one such methodology, namely a photocatalytic [2+2] cycloaddition reaction, to showcase how we employed property‐based computational analyses to guide the selection and validation of building blocks for the production of a library. Ultimately, these novel bond disconnections and design principles led to the assembly of a DNA‐encoded library that is composed of structurally diverse compounds within largely desirable property space and, therefore, well positioned to deliver novel chemical matter for drug discovery programs.

On the design of lead-like DNA-encoded chemical libraries

“…Recent advances in synthetic methodology suggest that this situation will improve further in the near future. [78][79][80][81][82][83][84] In addition to the need for chemistry compatible with DNA, an additional constraint for an ideal reaction for DEL construction is the ability to incorporate a monomer class that is populated with a large number of diverse, readily available compounds. Further diversity could be introduced using synthetic schemes that do not rely on a single scaffold.…”

Understanding Data Noise and Uncertainty through Analysis of Replicate Samples in DNA-Encoded Library Selection

“…A pool of 10 three-cycle DEL libraries was used in the TPL2 selection. All DELs were prepared at HitGen (8 Huigu First East Road, Chengdu, Sichuan, China, 610000) using a process of design, logistics, and synthesis similar to that outlined by Kolmel et al 6 The libraries were pooled targeting 1 × 10 6 copies of each individual molecule. In total, the pool contained ∼1.45 billion unique compounds.…”

“…DNA-Encoded Library (DEL) technology has emerged as an alternative approach , for lead discovery with several successful applications recently published. , To build upon this initial success, considerable effort has been dedicated to expanding DNA compatible chemistry, − improving DEL selection methods, ,, investigating new data analysis strategies, , and developing on-DNA hit confirmation techniques . Taken together, these emerging techniques have the potential to increase the number of confirmed hits derived from DEL selections.…”

Converting Double-Stranded DNA-Encoded Libraries (DELs) to Single-Stranded Libraries for More Versatile Selections

“… 3 , 4 In addition, DELs can access greater chemical space than biological display libraries, especially with the recent development of DEL-compatible reactions. 5 − 14 In the past decades, this technology has been widely adopted by the pharmaceutical industry and also showed potential as a powerful tool in academic research. 3 , 9 , 10 , 15 − 30 …”

“…In a DEL, each library compound is coupled with a unique DNA tag, which encodes its chemical structure and also acts as an amplifiable template for structural elucidation. Since the spatial encoding is replaced with DNA encoding in DELs, it allows the synthesis, processing, and selection of hundreds of millions to many billions of compounds in a single mixture at the minute scale (Figure a), and it does not require sophisticated equipment and logistics for compound handling and the selection can be done in a short time frame. , In addition, DELs can access greater chemical space than biological display libraries, especially with the recent development of DEL-compatible reactions. − In the past decades, this technology has been widely adopted by the pharmaceutical industry and also showed potential as a powerful tool in academic research. ,,,− …”